ABSTRACT In order to realize the promise of precision medicine, better biomarkers are needed to guide clinical decisions. New markers are needed to predict individuals at risk for developing a disease and thus may benefit from a particular intervention. Focusing on markers of mutagenesis is a promising strategy given that mutation is the ultimate source of all genetic variation, and mutated genes drive a number of important pathogenic processes, such as cancer. However, key elements are missing for evaluating mutagenesis in relation to disease risk. Absent are large-scale, well-characterized cohorts with high quality exposure data; populations with serial samples that have been collected and stored using uniform protocols; and the ability to robustly monitor somatic mutation in humans. We overcome these issues through a synergistic collaboration among clinicians, basic, computational, biostatistical, and population scientists that leverages an exceptionally sensitive next generation sequencing (NGS)-based mutational assay, which we recently developed; and its application to biological samples of the highest quality from both a clinical trial and the landmark Women?s Health Initiative (WHI) study. Our overarching goal is to contribute to the realization of the promise of precision prevention through completion of the following specific aims: 1) Monitor the kinetics of mutagenesis and selection across the human genome to identify robust mutational targets; 2) Examine the utility of somatic mutation induction as a biomarker of mutagenic exposure and its potential to stratify smokers that develop lung cancer versus those that do not; and 3) Test the utility of monitoring somatic mutation rate as a susceptibility/risk biomarker to identify individuals who will develop cancer. Overall, our proposal is innovative with respect to the technology used and its application to highly curated human samples. This project will highlight the potential utility of monitoring in vivo mutation induction to stratify cancer risk, providing a basis for directing medical intervention, lifestyle changes (i.e. limiting mutagen exposure), early diagnosis, and/or the application of chemopreventive measures with the potential to ultimately save lives.